This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. A unifying feature of cancer cells is an unstable genome. To achieve normal development, a cell must accurately coordinate pathways affecting DNA replication, chromosome segregation and DNA damage repair. Mishaps in any of these procedures can lead to instability in the genome and ultimately to a higher incidence of cancer development. Therefore, these mechanisms must be highly orchestrated and rigorously regulated. Accumulating evidence demonstrates that there are particular molecules that bridge these pathways to insure coordinate regulation. Many of these molecules have overlapping functions for DNA replication and repair and chromosome segregation. This study focuses on members of the RecQ helicase superfamily of proteins that function at replication forks and have roles in DNA repair and chromosome segregation. Bloom Syndrome is a recessive disorder resulting from mutation in the Bloom Syndrome gene (BLM) and characterized by increased genomic instability and enhanced onset of cancer. The physical and functional biochemical studies undertaken will identify and refine the sub-domains of Blm responsible for partnerships with known DNA repair and replication proteins to clarify the exact role of Blm in genomic stability. Furthermore, Chl1p is a newly identified RecQ family member in Drosophila and is implicated in bridging DNA replication and chromosomal cohesion. This study will identify the function of Chl1p in Drosophila by genetic deletion and mutations in Chl1p. Overall, the experiments span the disciplines of biochemistry, molecular biology and genetics to investigate the RecQ protein partnerships responsible for the accurate progression through DNA replication, repair and chromosome segregation.